Detecting Leaky Vessels in Cerebral Amyloid Angiopathy

We will use MRI and microscopy to detect subtle vessel fragility in patients who are at risk for large brain bleeds. Aim 1: We will assess subtle blood-brain barrier leakage with MRI in patients with cerebral amyloid angiopathy compared to a control group, and test whether this type of vessel fragility is associated with small brain bleeds. Aim 2: We will examine brain tissue of donor patients with cerebral amyloid angiopathy to examine blood vessel changes that are associated with blood-brain barrier leakage and small bleeds in great detail.

Extensive build-up of the protein amyloid-beta inside the walls of the small vessels of the brain can lead to hemorrhages in the brains of patients with dementia, and we suspect that blood-brain barrier (BBB) leakage is a potential mechanism underlying hemorrhagic lesion formation in these patients. We will combine state of the art magnetic resonance imaging techniques with detailed post-mortem examinations to explore associations between BBB leakage and subtle hemorrhagic brain pathology and cognitive functioning in patients with cerebral amyloid angiopathy. The success of this project will ultimately provide the field with a new tool to predict risk of hemorrhages in dementia at an early stage, which will be pivotal in the selection of individuals for amyloid-modifying therapies, and for the development of new drugs to prevent the formation of bleeds.

Although animal studies suggest that brain bleeds in cerebral amyloid angiopathy are the result of vessel wall breakdown, this has never been explored in in living humans. With state-of-the art MRI techniques we will now be able to determine, for the first time, whether there is an association between subtle brain bleeds and vessel wall fragility.

Cerebral amyloid angiopathy refers to deposition of the amyloid-beta protein in blood vessels in the brain, and is very common in patients with Alzheimer’s disease. The findings in this project will be of pivotal importance to the field of dementia as they will not only improve our understanding of the formation of brain bleeds in patients with cerebral amyloid angiopathy, but also potentially allow for the identification of individuals who are at risk for future bleeding, thereby offering an opportunity for timely intervention.